The new thioformamide derivatives of the present invention are those compounds of formula (I), hereinafter depicted wherein:
R represents an alkyl group; PA1 A represents either: PA1 Y represents: PA1 B represents either: PA1 wherein all alkyl groups and moieties, including those in alkoxy, alkoxycarbonyl and alkanoyl groups, can be straight-chain or branched, and, unless otherwise specified, contain one to four carbon atoms; PA1 and stereoisomers and salts thereof. PA1 i) R is a methyl group; PA1 ii) A is heteroaromatic and is preferably quinolin-3-yl or, more preferably, pyrid-3-yl; PA1 iii) Y is a methylene group; and PA1 iv) B is either: PA1 (1) vascular smooth muscle contraction including hypertension and other cardiovascular disorders such as congestive heart failure, and conditions associated with tissue ischaemia such as angina, peripheral vascular disease and cerebrovascular disease; PA1 (2) respiratory smooth muscle contraction including reversible airways obstruction and asthma; PA1 (3) contraction of smooth muscle of gastrointestinal tract, urinary bladder and uterus, including peptic ulcers, irritable bowel syndrome and diverticular disease; and premature labour.
(1) a phenyl group which is optionally substituted, preferably at the 3 and/or 5 position(s), by a halogen atom or a cyano, nitro, trifluoromethyl, carbamoyl, carboxyl, alkoxycarbonyl or alkylsulphonyl group and which may be further substituted by halogen atom(s), alkyl group(s), aryl-containing group(s) having six to twelve carbon atoms, or substituents which form a fused ring thereon; or PA2 (2) a heteroaromatic group containing 1 or 2 nitrogen atoms selected from pyrid-3-yl, quinolin-3-yl, isoquinolin-4-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrazin-3-yl, indol-3-yl and thiazol-5-yl, optionally substituted by an alkyl or alkoxy group, or a halogen atom; PA2 an ethylene or methylene group or a direct bond; and PA2 a) a phenyl, pyridyl, furyl or thienyl group, each of which may be optionally substituted by one or more substituents selected from halogen atoms; hydroxy, alkyl, C.sub.2-4 -alkenyl, alkoxy, phenoxy, tetrahydropyranyloxy, alkanoyl, benzoyl, cyano, nitro, trifluoromethyl, carboxy, amino, (optionally hydroxy)alkylamino, di(optionally hydroxy)alkylamino, trialkylammonio, alkoxycarbonylamino, alkanoylamino, benzoylamino, alkanoyloxy or alkoxycarbonyl groups; or carbamoyl groups (unsubstituted or substituted by one or two alkyl groups in turn optionally substituted by hydroxy groups, or by a straight- or branched chain divalent radical containing from 4 to 6 atoms in the chain and which may contain a further heteroatom (e.g. piperazino- or piperidino-carbonyl); or PA2 b) a straight- or branched-chain alkyl group (containing from 1 to 6 carbon atoms), alkenyl group (containing from 2 to 6 carbon atoms) or cycloalkyl group (containing from 3 to 6 carbon atoms), each of which may be optionally substituted by one or more substituents selected from halogen atoms; phenyl, naphthyl, imidazolyl or pyridyl groups (each optionally substituted as in a) above); hydroxy, C.sub.2-4 -alkenyl, alkoxy, phenoxy, tetrahydropyranyloxy, alkanoyl, benzoyl, cyano, nitro, carboxy, amino, (optionally hydroxy)alkylamino, di(optionally hydroxy)alkylamino, trialkylammonio, alkoxycarbonylamino, alkanoylamino, benzoylamino, alkanoyloxy or alkoxycarbonyl groups; or carbamoyl groups (unsubstituted or substituted by one or two alkyl groups in turn optionally substituted by hydroxy groups, or by a straight- or branched chain divalent radical containing from 4 to 6 atoms in the chain and which may contain a further heteroatom (e.g. piperazino- or piperidino-carbonyl), the cycloalkyl group optionally also bearing alkyl or trifluoromethyl groups; PA2 a) a pyridyl (preferably pyrid-3 or 4-yl), furyl (preferably furan-2-yl), thienyl (preferably thien-2-yl) or phenyl group each of which may be optionally substituted by one or more groups selected from halogen (preferably fluorine or chlorine) atoms or alkyl, alkoxy, trifluoromethyl, carboxy or dialkylamino groups; or PA2 b) an alkyl group (containing 1 to 6 carbon atoms), an alkenyl group (containing 2 to 6 carbon atoms) or cycloalkyl group (containing 3 to 6 carbon atoms) each of which may be optionally substituted by one or more hydroxy, alkoxy, phenoxy, tetrahydropyranyloxy, carboxy, amino, dialkylamino, trialkylammonio, alkoxycarbonyl, alkoxycarbonylamino, alkanoyloxy, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N'-alkylpiperazinocarbonyl or optionally substituted (preferably by benzoyl or nitro groups) phenyl or imidazolyl (preferably imidazol-1-yl) groups;
Particularly important classes of compounds of formula (I) exhibit one of more of the following features:
the other symbols being as hereinbefore defined, and their stereoisomers and pharmaceutically acceptable salts.
Particularly preferred values for B include phenyl, 2-, 3- or 4-fluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- or 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,5-bistrifluoromethylphenyl, 2-carboxyphenyl, 4-dimethylaminophenyl, pyrid-3 or 4-yl, furan-2-yl, thien-2-yl, methyl, propyl, t-butyl, benzyl, phenethyl, diphenylmethyl, 1-(3-benzoylphenyl)ethyl, 2-methyl-5-nitroimidazol-1-ylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, tetrahydropyran-2-yloxymethyl, cyanomethyl, 2-carboxyethyl, aminomethyl, 1-amino-2-phenylethyl, dimethylaminomethyl, trimethylammoniomethyl, 3-trimethylammoniopropyl, t-butoxycarbonylaminomethyl, acetoxymethyl, 2-methoxycarbonylethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N'-methylpiperazinocarbonyl)ethyl, 2-phenylethenyl, 1-cyano-2-phenylethenyl, cyclopropyl and 1-phenylcyclopropyl groups.
The presence of a carbonyloxy group on the ring creates an isomeric center in the molecule which in association with the adjacent asymmetric ring carbon atom leads to 4 stereoisomers which, optionally, can be separated into 2 racemic pairs The racemic pair and enantiomers in which the --OCOB and --CSNHR groups are in the trans relationship are preferred and the [1S,2R] enantiomers are particularly preferred.
In certain cases the substituents A, B, and R can also contribute to stereoisomerism. All such forms are also embraced by the present invention.
Particularly important compounds of the present invention include the following:
A (.+-.)-trans-2-Butanoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamid e PA0 B (.+-.)-trans-2-(4-Fluorobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecarb othioamide PA0 C (.+-.)-trans-N-Methyl-2-phenylacetoxy-1-(pyrid-3-yl)cyclohexanecarbothioam ide PA0 D (.+-.)-trans-2-(2-Carboxybenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecar bothioamide PA0 E (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-succinyloxycyclohexanecarbothioamid e PA0 F (.+-.)-trans-2-Acetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide PA0 G (.+-.)-trans-2-Benzoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide PA0 H (.+-.)-trans-N-Methyl-2-(pyrid-3-ylcarbonyloxy)-1-(pyrid-3-yl-)cyclohexane carbothioamide PA0 I (.+-.)-cis-2-Acetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide PA0 J (.+-.)-cis-2-Benzoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide PA0 K [1S,2R]-trans-2-Benzoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamid e PA0 L (.+-.)-trans-N-Methyl-2-(2-methylbenzoyloxy)-1-(pyrid-3-yl)cyclohexanecarb othioamide PA0 M (.+-.)-trans-2-(4-Chlorobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecarb othioamide PA0 N (.+-.)-trans-2-(3-Fluorobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecarb othioamide PA0 O (.+-.)-trans-2-(2-Fluorobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecarb othioamide PA0 P (.+-.)-trans-2-(3,4-Difluorobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamide PA0 Q (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(2-trifluoromethylbehzoyloxy)cycloh exanecarbothioamide PA0 R (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(3-trifluoromethylbenzoyloxy)cycloh exanecarbothioamide PA0 S (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(4-trifluoromethylbenzoyloxy)cycloh exanecarbothioamide PA0 T (.+-.)-trans-2-(3,5-Bistrifluoromethylbenzoyloxy)-N-methyl-1-(pyrid-3-yl)c yclohexanecarbothioamide PA0 U (.+-.)-trans-2-(3-Methoxybenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecar bothioamide PA0 V (.+-.)-trans-2-(4-Dimethylaminobenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohex anecarbothioamide PA0 W (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(3,4,5-trimethoxybenzoyloxy)cyclohe xanecarbothioamide PA0 X (.+-.)-trans-2-(4-Methoxybenzoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecar bothioamide PA0 Y (.+-.)-trans-N-Methyl-2-(pyrid-4-ylcarbonyloxy)-1-(pyrid-3-yl)cyclohexanec arbothioamide PA0 Z (.+-.)-trans-2-(2-Furoyloxy)-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioam ide PA0 AA (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(thien-2-oyloxy)cyclohexanecarbothi oamide PA0 AB (.+-.)-cis-2-Benzoyloxy-N-methyl-1-(quinolin-3-yl)cyclohexanecarbothioamid e PA0 AC (.+-.)-trans-2-Benzoyloxy-N-methyl-1-(quinolin-3-yl)cyclohexanecarbothioam ide PA0 AD [1R, 2S]-trans-2-Benzoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide PA0 AE cis/trans-[(2-N-methyl{thiocarbamoyl}-2-{pyrid-3-yl}cyclohexyloxycarbonyl) methyl]trimethylammonium chloride PA0 AF (.+-.)-trans-[3-(2-N-methyl{thiocarbamoyl}-2-{pyrid-3-yl}cyclohexyloxycarb onyl)propyl]-trimethylammonium chloride PA0 AG (.+-.)-trans-N-Methyl-2-[(2-methyl-5-nitroimidazol-1-yl-)acetoxy]-1-(pyrid -3-yl)cyclohexanecarbothioamide PA0 AH (.+-.)-trans-2-Acetoxyacetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioa mide PA0 AI (.+-.)-trans-N-Methyl-2-(1-phenylcyclopropylcarbonyloxy)-1-(pyrid-3-yl)cyc lohexanecarbothioamide PA0 AJ (.+-.)-trans-2-Diphenylacetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothio amide PA0 AK (.+-.)-trans-N-Methyl-2-(3-phenylpropenoyloxy)-1-(pyrid-3-yl)cyclohexaneca rbothioamide PA0 AL N,N-Dimethylglycine (.+-.)-trans-[N-methyl(thiocarbamoyl)]-2-(pyrid-3-yl)cyclohexyl ester PA0 AM (.+-.)-trans-2-[2-(3-benzoylphenyl)propanoyloxy]N-methyl-1-(pyrid-3-yl)cyc lohexanecarbothioamide PA0 AN (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-trimethylacetoxycyclohexanecarbothi oamide PA0 AO (.+-.)-trans-2-(3-Methoxycarbonylpropanoyloxy)-N-methyl-1-(pyrid-3-yl)cycl ohexanecarbothioamide PA0 AP (.+-.)-trans-2-Cyclopropanoyloxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarboth ioamide PA0 AQ (.+-.)-cis-2-Acetoxy-N-methyl-1-(quinolin-3-yl)cyclohexanecarbothioamide PA0 AR (.+-.)-trans-2-Acetoxy-N-methyl-1-(quinolin-3-yl)cyclohexanecarbothioamide PA0 AS (.+-.)-trans-2-(2-Cyano-3-phenylpropenoyloxy)-N-methyl-1-(pyrid-3-yl)cyclo hexanecarbothioamide PA0 AT (.+-.)-trans-2-Methoxyacetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioa mide PA0 AU (.+-.)-trans-N-Methyl-2-phenoxyacetoxy-1-(pyrid-3-yl)cyclohexanecarbothioa mide PA0 AV (.+-.)-trans-2-Cyanoacetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioami de PA0 AW (.+-.)-trans-N-Methyl-2-[3-(N-methylcarbamoyl)propanoyloxy]-1-(pyrid-3-yl) cyclohexanecarbothioamide PA0 AX (.+-.)-trans-N-Methyl-2-[3-(4-methylpiperazin-1-ylcarbonyl)propanoyloxy]-1 -(pyrid-3-yl)cyclohexanecarbothioamide PA0 AY (.+-.)-trans-N-Methyl-1-(pyrid-3-yl)-2-(tetrahydropyran-2-yloxy)acetoxycyc lohexanecarbothioamide PA0 AZ L-Phenylalanine (.+-.)-trans-[N-methyl(thiocarbamoyl)]-2-(pyrid-3-yl)cyclohexyl ester PA0 BA Glycine (.+-.)-trans-[N-methyl(thiocarbamoyl)]-2-(pyrid-3-yl)cyclohexyl ester PA0 BB (.+-.)-trans-2-Hydroxyacetoxy-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioa mide PA0 BC (.+-.)-trans-2-[3-(N,N-Dimethylcarbamoyl)propanoyloxy]-N-methyl-1-(pyrid-3 -yl)cyclohexanecarbothioamide PA0 BD (.+-.)-trans-N-Methyl-2-(3-phenylpropanoyloxy)-1-(pyrid-3-yl)cyclohexaneca rbothioamide PA0 BE (.+-.)-trans-2-t-Butoxycarbonylaminoacetoxy-N-methyl-1-(pyrid-3-yl)cyclohe xanecarbothioamide
as well as their stereoisomeric forms and pharmaceutically acceptable salts thereof
Letters A to BE are allocated to compounds for ease of reference in other parts of the specification.
The compounds have valuable pharmacological properties, in particular properties which are indicative of utility in the treatment and/or prophylaxis of disorders associated with:
The compounds also have utility in the inhibition of head hair loss associated with male pattern baldness, by topical application.
For example, compounds of general formula (I) were submitted to: